CANDIDATE: Matthew J. Rossman, Ph.D., is a new postdoctoral fellow in Integrative Physiology at the University of Colorado Boulder. In this NRSA application, Dr. Rossman seeks to conduct innovative translational research providing new insight into the efficacy of a novel mitochondria targeted antioxidant, mitoquinone (MitoQ), for reducing endothelial reactive oxygen species production by mitochondria (mtROS) and improving vascular function in late middle-aged and older (MA/O) adults. His immediate goal is to acquire the research training and professional skills necessary to transition to an independent investigator. His long-term goal is to become an extramurally funded scientist focusing on translational strategies to enhance cardiovascular function and reduce the risk of cardiovascular diseases with aging. CAREER DEVELOPMENT PLAN: Dr. Rossman's career development plan consists of: 1) acquiring new experimental techniques and approaches to strengthen his research skills; 2) further training in biostatistics; and 3) professional skills development via formal course work; attendance and presentations at weekly journal clubs, university seminars, and national scientific meetings; and regular interactions with his mentoring team. ENVIRONMENT: The environment for Dr. Rossman's training plan should be outstanding. The principal mentor, Dr. Seals, is an internationally recognized and NIH funded scientist with a strong record of successful mentoring in translational biomedical research pertaining to preservation of vascular function and health with aging. Consulting-mentor Dr. McQueen is director of biostatistics in several research centers on campus. Consulting-mentor Dr. Murphy is a biochemist and the developer of MitoQ, and therefore will be able to provide unique insight regarding its biological actions. RESEARCH: Age-related vascular endothelial dysfunction, characterized by impaired endothelium-dependent dilation (EDD), is caused by reduced nitric oxide (NO) bioavailability secondary to oxidative stress. A major contributor to age-associated vascular oxidative stress is excessive production of mtROS. MitoQ accumulates in the mitochondria and reduces mtROS in vivo. Preclinical findings from our lab indicate that 4 weeks of MitoQ supplementation in mice reverses age-related endothelial dysfunction by normalizing vascular mitochondrial superoxide production and oxidative stress. The goal of the proposed research is to translate these preclinical findings to humans by conducting a randomized, double-blind, placebo-controlled, cross-over pilot study to provide the first evidence for the efficacy of oral MitoQ supplementation to improve NO-mediated EDD in healthy MA/O adults with baseline endothelial dysfunction (Aim 1). To elucidate mechanisms responsible for the beneficial effects of MitoQ, I will assess endothelial cell mtROS production, mtROS-mediated suppression of EDD, and systemic and/or vascular endothelial cell markers of mitochondrial function, oxidative stress, and inflammation. I will also determine the role of changes in pro- and anti-oxidant proteins with loss of function cell culture studies (Aim 2).